LabConsiimer
`
`Some Like It Hot: A Thermal Cycler Roundup
`
`Former high—endfeatures are standard
`options in the newest thermal cyclers
`Bv AILEEM CoIirs'rA|us
`
`lids featuring automatic
`pressure control
`for reli-
`able sealing and protection
`of tubes.
`
`It was bound to happen. During the growth of PCR,
`
`many companies joined the thermal cycler bandwagon.
`But since The Scientisfs last thermal cycler review,1
`some of these manufacturers—such as Ericomp—have left
`the cut-throat market and a number of the machines listed
`in previous LabConsumer profiles have been discontinued.
`Market niches remain for those companies and product
`lines that have survived the intense competition.
`One such niche is real-time therrnocyclers, previously
`reviewed in The Scientist? These cyclers permit
`researchers to monitor the thermal and optical properties
`of their reactions in real time, and are indispensable for
`quantitative PCR. Another specialty is high-throughput
`PCR, spurred by the rapid growth of genomics—related
`research. Overall, features that were once optional, such
`as heated lids, are now standard, and interchangeable
`blocks allow researchers to customize their experiments
`even with low—end thermal cycler models.
`Although the number of companies manufacturing
`thermal cyclers may be on the decline, the number of
`options available to researchers is not. From basic labo-
`ratory PCR workhorses to real-time and high-throughput
`machines, the latest batch of thermal cyclers will certain-
`ly heat
`things up in the lab this coming year. What
`follows is an alphabetical
`round up of thermocycler
`providers:
`
`Applied Biosystems: Foster City, Calif.-based Applied
`Biosystems holds the patents on thermal cyclers, along
`with the exclusive license to the PCR process} and offers
`researchers several PCR options. The GeneAmp® PCR
`System 9700 is designed for high sample volumes and
`comes in 60-well/0.5 ml, 384-well, and 96-well formats.
`The GeneAmp PCR System 2400 is a personal-sized
`cycler that features a heated lid and a 24-well sample
`block. The GeneAmp PCR System 2700 includes many
`of the features of the 9700 system but
`in a smaller
`footprint. For
`the real-time PCR market, Applied
`Biosystems’ ABI PRISM® 7700 Sequence Detection
`System features a built—in thermal cycler and the ability
`to detect multiple fluorophores in a single tube.
`
`Biometra: Gottingen, Germany-based Biometra offers a
`variety of Peltier—based cyclers, ranging from personal-
`sized to high throughput. (The Peltier effect transfers
`heat from one side of a semiconductor to another, creat-
`ing an efficient heating and cooling system without
`refrigerants or compressors.) The Tpersonal thermocy—
`cler
`features three different block formats—48—well,
`20-well, and combi-block. Each format handles tubes,
`strips, and microplates. The TGradient
`themiocycler
`allows fast optimization of new reactions with a thermal
`gradient of up to 40°C. The TI thermocycler offers a
`heated lid, gold—plated silver block, and heating and cool-
`ing rates of 4°C per second and 3°C per second,
`respectively. The T3 therrnocycler, the successor to the
`company’s TRIO model, offers a choice of three fonnats:
`3 x 48 wells, 3 x 20 wells, and a combi-block with 3 x 18
`and 3 x 48 wells. The T3 also features three independent
`blocks with adjustable heated lids, allowing the user to
`run experiments with different sample sizes and formats
`in the same instrument. The TROBOT thermocycler is the
`newest addition to Biometra’s cycler range. It is compat-
`ible with a variety of robotic systems and offers a
`motorized heated lid and a small footprint. The motor-
`ized plate lifter ensures easy removal of plates by a
`robotic arm. All Biometra thermal cyclers have heated
`
`32 The Scientist
`December 10, 2001
`
`Bio-Rad Laboratories:
`Hercules,
`Calif.-based
`Bio—Rad
`offers
`the
`iCyclerTM Thermal Cycle,
`a flexible, modular system
`that easily upgrades to real-
`time
`quantitative
`PCR
`capability and also offers
`optional gradient capability to
`facilitate reagent optimization.
`The optical real-time detection
`system upgrade is a modular unit
`that installs directly over an existing or new iCycler unit.
`The resulting iCycler iQ system is designed as an open
`platform, capable of detecting a variety of different
`chemistries,
`including DNA binding dyes, Roche
`Molecular Systems’ TaqMan®, molecular beacons, dual
`FRET, and primer-based technologies. The optical design
`promotes the multiplexed analysis of up to four different
`fluorophores without compromising sensitivity or
`dynamic range. Bio—Rad also offers a personal-sized
`cycler, the Gene Cycler, which features a small footprint
`and a heated lid.
`
`Brinkmann Instruments: Westbury, N.Y.-based
`Brinkmann’s Eppendorf® Mastercycler® line of thermal
`cyclers includes both personal-sized and gradient mod-
`els. All feature heated lids and are sold with a PCR
`license. The gradient model provides constant ramping
`rates (SteadySlopeTM technology) so that programs opti-
`mized on the instrument can be used on non—gradient
`machines.
`
`Cepheid: According to company president Kurt
`Petersen, Sunnyvale, Calif.-based Cepheid has sold
`more than 400 Smart Cycler® instruments since the
`product was launched in May 2000. The system is based
`on the company’s I—CORE® technology!microfluidics-
`based, temperature—controlled modules that permit each
`sample to be subjected to different experimental condi-
`tions. Petersen explains that the Smart Cycler is the only
`real-time system on the market that offers this “random
`access” capability, a feature that speeds up assay opti-
`mization by allowing researchers to operate each reaction
`site independently of the others. Each I-CORE unit can
`examine up to four targets in a reaction tube, thus facili-
`tating multiplex reactions.
`
`Corbett Research: For gadget-loving researchers,
`Corbett Research of Sydney, Australia offers the Palm
`Cycler, an individual—sized thermal cycler integrated with
`a Palm PC. The instrument offers a gradient function fea-
`turing a true gradient from l—8 degrees across the block.
`Corbett’s Rotor-Gene, a real-time PCR system, can
`detect a variety of chemistries including SYBR Green I
`(from Eugene, Ore.—based Molecular Probes), TaqMan,
`and molecular beacons, and can detect four different flu-
`orescent probes in a single tube. The Rotor—Gene
`maintains temperature homogeneity via a centrifuge
`rotor that spins the samples at 500 rpm.
`
`Idaho Technology Inc.: This Salt Lake City based com-
`pany’s latest offering is the Indym Air Thermocycler,
`which uses air cycling to decrease ramping and cooling
`time; a 30-cycle, three-temperature reaction can be com-
`pleted in less than 35 minutes. Unlike the company’s
`flagship RapidCycler®, which uses a similar cycling
`technology but is limited to capillary tubes, the Indy ther-
`
`
`
`CourtesyofBrinkmannInstruments
`
`Brinkmann's Eppendorf Mastercycler line of thermal
`cyclers includes gradient and personal-sized models.
`
`mocycler is designed for ‘standard 24 x 0.2-ml PCR
`tubes. According to company representative Nathaniel
`Lallatin, the Indy thermocycler’s speed and small foot-
`print make it
`ideal for research laboratories that are
`trying to increase throughput but do not wish to invest in
`a more expensive,
`large-capacity machine.
`Idaho
`Technology’s popular RapidCycler model is still avail-
`able and is actually faster than the Indy cycler owing to
`the higher heat conductivity of glass capillary tubes;
`however, researchers may find that standard PCR tubes
`are easier to use.
`
`Marsh Bio Products: Rochester, N.Y.-based Marsh
`offers two Duncan thermal cyclers, each utilizing a water
`bath for thermal control. The DT-24 and DT-108 instru-
`ments can accommodate 24 or 108 microtiter plates
`respectively. Since these instruments use water baths for
`temperature control, they exhibit small well—to-well tem-
`perature variability, according to David Witkoski,
`Marsh's marketing communications manager. The
`Duncan thermal cyclers are robotic-based and are mostly
`found in pharmaceutical and biotechnology companies.
`
`MatriCal: Chadds Ford, Pa.-based MatriCal developed
`the MatriCyclerTM for
`the company’s
`specialized
`MatriPlatesTM, which are designed to optimize the shape
`of high-throughput wells for increased signal detection
`and ease of liquid handling. According to company liter-
`ature, researchers using the MatriCycler with the plates
`can increase their throughput up to 100 percent, with a
`reduction in reagent use of approximately 80 percent.
`Company co-founder Kevin Oldenburg explains that the
`MatriCycler overcomes four problems associated with
`the use of traditional cyclers for high-throughput experi-
`ments. First, the heating block of a conventional cycler is
`a large thermal mass that takes a long time to heat and
`cool. Similarly, the plastic used in multi-well plates is
`thermally insulated and therefore takes time to heat.
`Because plastic tends to deform upon heating, the plates
`tend to warp and become wedged into the machine, pre-
`venting easy removal. Finally, reactions using multi-well
`plates require the use of a heated lid to prevent evapora-
`tion;
`this often results
`in the development of a
`temperature gradient across the plate.
`The MatriCycler works by heating each sample well
`with a thermally conductive probe, rather than relying on
`the thermal block to heat the samples. This eliminates the
`problem of sample evaporation, speeds up sample heat-
`ing, and, according to Oldenburg, provides a heating rate
`of up to 20°C per second. Thus, a 30-cycle reaction takes
`20-30 ntinutes to complete with this instrument.
`
`MJ Research Inc.: MJ Research (MJR) of Waltham,
`Mass., has added a number of new items to the world of
`thermal cyclers. All of the company’s cyclers feature
`Peltier heating and Alpham modules,
`interchangeable
`
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`THERMO FISHER EX. 1014
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`

`
`heating blocks that allow users to change sample format
`rapidly. MJR offers 10 different Alpha units for formats
`ranging from 0.5-ml PCR tubes to microwell plates to
`microscope slides; one of the more unique products is a
`set of microscope slide blocks that allow users to run a
`total of 32 slides at a time for in situ PCR. The DNA
`Engine” cycler, the company’s “workhorse” model, fea-
`tures a heated lid and independent dual blocks to allow
`two experiments to be run simultaneously. The Dyadm
`thermal cycler, one of the newest members of the MIR
`family, allows four separate protocols to be run at the
`same time with the use of two Alpha modules. It also fea-
`tures an easy—to—use, Windows—driven, graphical user
`interface. The newer Tetradm model offers the same fea-
`tures as the smaller DNA Engine” cycler, but is capable
`of handling four times as many samples. All units feature
`a heated lid and are robotic—compatible. For more modest
`budgets, MJR offers a number of personal—sized cyclers,
`including the Mini—Cycler and PTC—l00TM thermal
`cycler. These cyclers feature Hot Bonnetm heated lids
`and can be used for a variety of sample formats.
`MJR‘s recently released DNA Engine Opticonm is a
`real-time cycler that uses fluorescent detection to moni-
`tor reactions. The system is essentially a DNA Engine
`chassis coupled to a 96-well Alpha unit and an optical
`detector. According to vice president of sales and mar-
`keting Mike Mortiliaro, the Opticon is the only 96-well
`real time system on the market that involves no moving
`parts yet allows the instrument to view each sample or
`well independently. A photomultiplier tube detects sig-
`nals from samples individually. “One of the big
`advantages that we see in the Opticon’s design is that
`we‘re looking at each sample independently and individ-
`ually, and we have much lower cross-talk. That gives us
`a broader dynamic range and a higher level of sensitivi-
`ty,” says Mortillaro.
`
`MWG-Biotech AG: Ebersburg, Germany—based MWG,
`offers the Primus system, a multi-block cycler that is
`designed as a four-block, stand-alone unit but can also be
`interfaced with up to 30 individual blocks via PC soft-
`ware. The system also features a patented high-pressure
`lid that, unlike other heated lids, prevents evaporation of
`reaction volumes from 384-well plates. Standard heated
`lids were developed to promote temperature homogeneity
`across the block, but were designed when scientists were
`still using individual rriicrofuge tubes with caps, says
`Craig Abrahams, president of High Point, N.C.—based
`MWG Biotech Inc.,
`the company‘s U.S. subsidiary.
`However, in today's higher-throughput market where sci-
`entists use rnicroplates,
`they cannot be fully sealed or
`capped easily. “So these same heated lids
`are now pro-
`moting evaporation," explains Abraharns. The Primus
`cycler’s high-pressure lid provides up to 300 Newtons of
`pressure, making it effective for evaporation protection.
`According to Abrahams, the Primus system has been pop-
`ular with high-throughput labs looking for high capacity
`instruments at a low cost. For example, Graham Casey,
`a researcher at
`the Cleveland Clinic Foundation in
`Cleveland, Ohio, recently purchased three of the multi-
`block instruments and says that he has been “pleased with
`all of the machines.” Laura Bedzyk, staff biologist at
`Wilmington, Del.-based DuPont Co., has been using the
`Primus thermocycler in her research for almost two years
`for generating PCR products for DNA microarrays;
`Bedzyk says that the factors influencing her decision to
`purchase this instrument included “multiple, independent
`positions, pressurized lids, ease of use, and the potential
`for incorporation into a custom, automated system.”
`
`Indianapolis-based
`Roche Molecular Biochemicals:
`Roche has licensed Idaho Technology’s thermal cycler
`technology and reengineered it for the LightCyclerTM
`instrument, a real-time thermal cycler that, like Idaho’s
`RapidCycler, employs circulating air and glass capillary
`tubes to dramatically reduce amplification time. The sys-
`tem uses fluorescent detection for real-time analysis and
`is controlled by a PC workstation. Researchers can use
`the LightCycler for assays using SYBR Green I,
`
`LabConsumer
`
`Roche's Lightcycler instrument uses circulating air and
`glass capillary tubes to reduce amplification time.
`
`sequence-specific hybridization probe pairs, or several
`other detection formats?
`
`St. John Associates: Beltsville, Md.-based St. John’s
`BioOven III Therrnocycler is based on circulating air
`technology but is capable of handling samples in a vari-
`ety of formats,
`including standard PCR tubes, glass
`capillary tubes, slides, and multiwell plates. Designed
`for very high capacity, the BioOven III cycler can han-
`dle 10 multi—well plates per run and features a rotating
`carousel to ensure temperature uniformity. According to
`Peter St. John, the BioOven III cycler enjoys populari-
`ty with scientists in a variety of fields including
`agribusiness, forensics, and pharmaceutical research,
`because it offers greater well-to-well uniformity than
`aluminum block cyclers and provides higher flexibility
`in terms of sample media.
`
`Jolla, Calif.—based Stratagene’s
`Stratagene: La
`RoboCycler
`features four programmable blocks and
`offers a gradient feature to simplify optimization. What
`makes this cycler unique is that it employs a robotic arm
`to move samples from block to block. The user can set
`three of the four blocks to denaturation, annealing, and
`polymerization temperatures; the fourth is a cooled stor-
`age block. Because samples are moved robotically to the
`appropriate temperature block for each point in the reac-
`tion, there is no need for temperature ramping of a given
`block. According to company literature,
`this method
`reduces experiment time up to 30 percent. Product man-
`ager Peter Pingerelli explains that the popularity of the
`RoboCycler stems from its durability. Competing instru-
`ments, he says, “have had a lot of problems, with
`heavy—use instruments [failing] post-warranty.”
`Stratagene’s Mx4000TM Multiplex Quantitative PCR
`System, introduced last year? offers fluorescence-based
`real-time detection and can measure up to four different
`dyes in a single tube. The system uses a quartz-tungsten
`halogen lamp rather than a laser light source, broadening
`the excitation wavelength range. It also features a PC
`interface and, according to company literature, tempera-
`ture control that exceeds the industry standard.
`
`Techne: Princeton, N.J.-based Techne offers a range of
`cyclers to fit different research needs and budgets. The
`Techgene® cycler, a Peltier—based system that replaces
`the company’s Progene® model, is a compact, inexpen-
`sive instrument that researchers can run remotely through
`a PC. Although the Techgene cycler is designed for a low
`sample quantity (20-25 wells), up to 32 units can be
`linked for larger experiments. The Flexigene® cycler,
`which will replace the company's Genius® model, is a
`Peltier—based system designed for higher throughput.
`
`Techne’s Touchgene® Gradient Thermal Cycler is adver-
`tised as the most linear gradient cycler on the market—it
`is linear over a 30°C rarige—and offers real-time graphi-
`cal display and a touch-sensitive screen for ease of
`programming. To
`ensure
`block
`uniformity,
`the
`Touchgene cycler includes four temperature sensors per
`block. All Techne cyclers come standard with adjustable
`heated lids and interchangeable blocks.
`
`Thermo Hybaid: Franklin, Mass.-based Thermo
`Hybaid’s cyclers, which range from individual-sized to
`multi-block networks, come in a variety of formats.
`The company’s most basic system, the PCR Sprint, fea-
`tures Peltier heating, a 20-24 sample individual block,
`and two different block format options. Thermo
`Hybaid’s PCR Express and soon-to-be-released Pxll,
`also Peltier—based machines, feature six different inter-
`changeable block options, including a flat block for in
`situ or microarray experiments. The PxII also includes
`Thermo I-lybaid’s new fast block technology and a
`large graphical display panel.
`The company's MultiBlock System (MBS) is a flexi-
`ble thermal cycler system driven and monitored by a
`central PC that features software, which allows real-time
`monitoring and automatic logging for good laboratory
`practice (GLP) purposes. By enabling up to 30 individual
`blocks to be attached to a single processor, users pay less
`per block than they would if purchasing individual stand-
`alone machines. And, unlike the multi-block systems
`from MJR and MWG, Thermo Hybaid’s system allows
`the user to purchase blocks individually. The company’s
`newest product
`is
`the MBSR,
`the fully robotic
`MultiBlock, which facilitates high-throughput PCR.
`According to the company, by ejecting the whole block
`through the front of the unit, the MBSR is fully stackable
`and integrates easily into robotic systems. 53
`Aileen Constans can be contacted at
`aeonstans@the-sciemistrom.
`References
`1. G. Meisenholder, “New lids on the block,“ The Scientist, l3[23]:l7,
`Nov. 22, 1999.
`2. D. Fitzgerald, “Up to speed on PCR," The Sciemis/. l4[23]:3l, Nov.
`27. 2000.
`3. A. Constans, “Courts cast clouds over PCR pricing," The Scientist,
`l5[l7]:l, Sept. 3, 2001.
`
`St. John's BioOven III thermocycler offers
`flexibility in terms of sample formats.
`
`The Scientist 33
`December 10, 2001
`
`2 OF 5
`
`THERMO FISHER EX. 1014
`
`

`
`LabConsumer
`
`Suppliers of Thermal Cyclers
`
`836
`<z’~°
`
`Gonchnp KR S-Nam 9700 *
`
`Banedmu KR Syylem Z700
`
`Ganadmp Kl Symm 2400
`T7
`
`T3 fllevmocyclev
`
`Yfimfielll
`
`II Ibemvotycler
`
`Ipersonnl
`
`i(ydar
`
`Gene (ydev
`
`Mns1:|(y~:|ev
`
`Muslntyrlnr limdiml
`
`Musiertyder Pusamll
`
`Mnslmythv 384
`
`Smorl (ytlzr Vysilm
`
`Palm (ythr
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`
`Mnsm(yder 334
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`GTE-1 (Sunni: Thnnnul
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`
`Indy Air flgevmnryclev
`
`Fellier
`
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`cunling
`
`Applied Biosystems
`(800) 345-5224
`www.app|iedbiosystems.com
`
`Biometra
`+ 49 (S51) 50 68 6 O
`www.biometra.com
`
`Bio—Rad
`(800) 424-6723
`www.bio-rad.com
`
`Brinkmann
`(800) 645-3050
`www.brinkmann.com
`
`Cepheid
`(888) 838 3222
`www.smartcyc|er.com
`Corbett Research
`+61(2) 9736 1320
`www.corbettresearch.com
`
`GL Applied Research
`(847) 223-2220
`Hnzmh
`’
`rm
`
`Idaho Technology
`(800) 7356544
`www.idahotech.c0m
`
`34 The Scientist
`December 10, 2001
`
`6‘)
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`
`Alnbienl In 99°(
`
`3 OF 5
`
`THERMO FISHER EX. 1014
`
`

`
`LahConsumer
`
`Suppliers of Thermal Cyclers (continued)
`
`Amhielll Io 9b°(
`
`lllumm DI-1Ill Bnbufl: Syslem
`
`‘ Dunmn DI-24 Rnlmlit Sysiun
`
`Mulrityder
`
`Dill Bruin:Themnl (ydu
`
`DNA Engine Dyud (yder
`
`IJIIA Engine Ietmd (yder
`
`PIC-I00 Tllanml Eytler
`
`Minifyth
`
`lighitytler Sysvum
`
`lliolhen Ill
`
`-
`
`'
`
`.
`
`Amhilnl to 100°C
`
`Mofydev Tempemun (ytlov
`(40/96]
`
`Blotks 14: mm
`Blotk 4: Pehier tooling
`
`llnhofytlev Gmdiam Iempemlura
`(yflcrs (4/95)
`
`Blozks I-3: Resistive
`almk 4: Fairer mnling
`
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`
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`
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`
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`swam
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`
`Editor's Note: To the best of our knowledge, this table is a comprehensive listing of suppliers.
`
`The Scientist
`December 10, 2001
`
`4 OF 5
`
`THERMO FISHER EX. 1014
`
`

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